Targeting of cells expressing wild‐type EGFR and type‐III mutant EGFR (EGFRvIII) by anti‐EGFR MAb ICR62: A two‐pronged attack for tumour therapy

Modjtahedi, Helmout; Moscatello, David K.; Box, Gary; Green, Margaret; Shotton, C; Lamb, David; Reynolds, Lesley J.; Wong, Albert J.; Dean, Christopher; Thomas, Hilary; Eccles, Suzanne A.

doi:10.1002/ijc.11055

Cited by 55 publications

(41 citation statements)

References 37 publications

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“…These conflicting results raise cautions and demands for further investigation of potential therapeutic benefit by dual targeting of the EGFR with anti-EGFR mAbs and the EGFR TKIs. In addition, because anti-EGFR mAbs such as cetuximab or ICR62 could inhibit the growth of EGFR-expressing tumor cells via immunologic mechanisms, such as antibody-dependent cellular cytotoxicity (26,31), the results of ongoing clinical trials should unravel whether such combinations are antagonistic or associated with more side effects in patients with cancer (50).…”

Section: Discussionmentioning

confidence: 99%

“…Of these, mAb ICR62 blocks the binding of ligands to the EGFR and subsequent phosphorylation of the EGFR, and inhibits the growth of several EGFR-overexpressing (e.g., head and neck, breast, and vulva) cell lines both in vitro and in vivo (29). In addition, mAb ICR62 has been shown to inhibit the growth in vivo of EGFRvIII-expressing tumors by mediating antibody-dependent cellular cytotoxicity and localization to metastatic lesions in cancer patients 24 hours after administration (30,31). The aim of this study was to evaluate the sensitivity of a panel of human colorectal tumor cell lines to treatment with anti-EGFR mAb ICR62 used alone and in combination with gefitinib.…”

Section: Introductionmentioning

confidence: 99%

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Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

Cunningham

Thomas

Fan³

et al. 2006

Cancer Research

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The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensitivity of 10 human colorectal tumor cell lines (DiFi, CCL218, CCL221, CCL225, CCL227, CCL228, CCL231, CCL235, CCL244, and HCT-116) to treatment with our anti-EGFR monoclonal antibody, ICR62, and/or the EGFR tyrosine kinase inhibitor, gefitinib. Of the cells examined, only DiFi contained high levels of constitutively active EGFR and were highly sensitive to treatment with both ICR62 (IC 50 = 0.52 nmol/L) and gefitinib (IC 50 = 27.5 nmol/L). In contrast, the growth of other tumor cell lines, which contained low levels of the EGFR, HER-2, and pAkt but comparable or even higher basal levels of phosphorylated mitogen-activated protein kinase (pMAPK), were relatively resistant to treatment with both inhibitors. Both ICR62 and gefitinib induced EGFR down-regulation, reduced the basal levels of pEGFR at five known tyrosine residues, pMAPK, and pAkt, and increased the sub-G 1 population in DiFi cells. However, treatment with a combination of ICR62 and gefitinib neither sensitized colorectal tumor cells that were insensitive to treatment with the single agent nor enhanced the growthinhibitory effect of the single agent in DiFi cells. These results indicate that basal levels of pMAPK and pAkt are not good indicators of response to the EGFR inhibitors in colorectal cancer cells and dual targeting of the EGFR by a combination of ICR62 and gefitinib is not superior to treatment with a single agent. (Cancer Res 2006; 66(15): 7708-15)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

Cunningham

Thomas

Fan³

et al. 2006

Cancer Research

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“…38). In addition, ICR62 has been shown to bind effectively to cells expressing wild-type EGFR and EGFR variant III (39). The humanized GA201 construct showed identical EGFR-binding behavior as the parental rat antibody.…”

Section: Engineering and Characterization Of Ga201mentioning

confidence: 99%

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

Gerdes

Nicolini

Herter

et al. 2013

Clinical Cancer Research

110

109

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Purpose: Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG 1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells.Experimental Design: We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcgRIIIA.Results: In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low-and high-affinity variants of FcgRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan).Conclusions: These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors.

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“…EGFRvIII was first identified in a subset of gliomas and has since been found in some non-small-cell lung carcinomas (Okamoto et al, 2003) and breast carcinomas (Rae et al, 2004), but not on normal cells. mAbs specific for this variant form of EGFR but unreactive with the wild-type EGFR have been reported (Reist et al, 1995;Wikstrand et al, 1995;Archer et al, 1999;Beers et al, 2000;Modjtahedi et al, 2003;Omidfar et al, 2004) and advanced development of this mutant receptor as a target is implemented.…”

Section: Naked Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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Targeting of cells expressing wild‐type EGFR and type‐III mutant EGFR (EGFRvIII) by anti‐EGFR MAb ICR62: A two‐pronged attack for tumour therapy

Cited by 55 publications

References 37 publications

Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

Responses of Human Colorectal Tumor Cells to Treatment with the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib

GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab

Novel antibodies as anticancer agents

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